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Help with HepatologyHelp with Hepatology
Spire 2013Spire 2013
Dr Allister J GrantDr Allister J GrantConsultant HepatologistConsultant Hepatologist
Leicester Liver UnitLeicester Liver UnitUniversity Hospitals Leicester NHS TrustUniversity Hospitals Leicester NHS Trust
Abnormal LFT’s in well patientsAbnormal LFT’s in well patients
1)1) Isolated raise in bilirubinIsolated raise in bilirubin
2)2) γGT raisedγGT raised
1)1) ALT rise predominant ALT rise predominant
2)2) ALP rise predominantALP rise predominant
1) Isolated raise in bilirubin1) Isolated raise in bilirubin
DifferentialDifferential Gilberts vs HaemolysisGilberts vs Haemolysis
Gilberts- Gilberts- unconjugated hyperbilirubinaemiaunconjugated hyperbilirubinaemia
Haemolysis-Haemolysis-Unconjugated hyperbilirubinaemiaUnconjugated hyperbilirubinaemia
splenomegaly, anaemia , splenomegaly, anaemia , DCT, haptoglobin, reticulocyte count, filmDCT, haptoglobin, reticulocyte count, film
2) 2) -Glutamyl transpeptidase-Glutamyl transpeptidase
The high sensitivity and very low specificity seriously The high sensitivity and very low specificity seriously hampers the usefulness of this testhampers the usefulness of this test
If ALP is elevated and GGT is elevated then the raise in If ALP is elevated and GGT is elevated then the raise in ALP is likely to be hepatic in originALP is likely to be hepatic in origin
Elevated in Elevated in a whole host of liver diseasesa whole host of liver diseases Drugs/AlcoholDrugs/Alcohol Obesity/ dyslipidaemia/ DMObesity/ dyslipidaemia/ DM CCFCCF Kidney, Pancreas, ProstateKidney, Pancreas, Prostate
The majority of abnormal LFTs in The majority of abnormal LFTs in asymptomatic people occur in those with:asymptomatic people occur in those with:
Diabetes or metabolic syndrome Diabetes or metabolic syndrome (increased risk of NAFLD) (increased risk of NAFLD)
Excessive alcohol intake Excessive alcohol intake Chronic hepatitis B Chronic hepatitis B Chronic hepatitis C Chronic hepatitis C DrugsDrugs
2) ALT rise predominant2) ALT rise predominant2) ALT rise predominant2) ALT rise predominant
Case - Case - Mr ZMr Z
59y Architect59y Architect
Type 2 DM 15 yrs on diet aloneType 2 DM 15 yrs on diet aloneBMI 35BMI 35HypertensionHypertension
Amlodipine , RamiprilAmlodipine , Ramipril
Minimal AlcoholMinimal Alcohol
Mr RPMr RP
Generally unwell for 2 yearsGenerally unwell for 2 years CytopaeniaCytopaenia
Low Hb/plateletsLow Hb/platelets Normal haematological Ix (peripheral Normal haematological Ix (peripheral
consumption)consumption)
May 07May 07 LGH admission with ataxia/drowsinessLGH admission with ataxia/drowsiness Extensive IxExtensive Ix
Mr RPMr RP
CT abdoCT abdo cirrhotic liver, portal hypertension, splenomegalycirrhotic liver, portal hypertension, splenomegaly
OPD referralOPD referral Alb 28, Pl 65 LFT’s normal, INR 1.5Alb 28, Pl 65 LFT’s normal, INR 1.5 Imaging compatible with cirrhosisImaging compatible with cirrhosis Reversal of sleep pattern, lack of concentrationReversal of sleep pattern, lack of concentration Daytime somnelence, intermittant confusionDaytime somnelence, intermittant confusion OGD- varicesOGD- varices
How common is NAFLD?How common is NAFLD?How common is NAFLD?How common is NAFLD?
The most common cause of abnormal liver function The most common cause of abnormal liver function tests in the United States.tests in the United States.
Estimated 30.1 million with NAFLD and 8.6 million Estimated 30.1 million with NAFLD and 8.6 million with NASHwith NASH
Affects 10-24% of the populationAffects 10-24% of the population 58-74% of the obese population58-74% of the obese population Affects 2.6% of childrenAffects 2.6% of children 23-53% of obese children23-53% of obese children
LEICEST
ER
SteatosisSteatosis
SteatohepatitisSteatohepatitis
CirrhosisCirrhosis
Hepatocellular carcinoma
Hepatocellular carcinoma
Non Alcoholic Fatty Liver Disease (NAFLD)Spectrum of Hepatic Pathology
Non Alcoholic Fatty Liver Disease (NAFLD)Spectrum of Hepatic Pathology
Diseases Associated with SteatohepatitisDiseases Associated with Steatohepatitis
1.Alcoholism1.Alcoholism2.Insulin resistance2.Insulin resistance a.Metabolic Syndromea.Metabolic Syndrome
i.Obesityi.Obesityii.Diabetesii.Diabetesiii.Hypertriglyceridemiaiii.Hypertriglyceridemiaiv.Hypertensioniv.Hypertension
b.Lipoatrophyb.Lipoatrophy c.Mauriac Syndromec.Mauriac Syndrome d.PCOSd.PCOS3.Disorders of lipid metabolism3.Disorders of lipid metabolism a.Abetalipoproteinemiaa.Abetalipoproteinemia b.Hypobetalipoproteinemiab.Hypobetalipoproteinemia c.Andersen’s diseasec.Andersen’s disease d.Weber-Christian syndromed.Weber-Christian syndrome4.Total parenteral nutrition4.Total parenteral nutrition5. HCV 5. HCV (certain genotypes)(certain genotypes)6. Untreated coeliac disease6. Untreated coeliac disease
7.Severe weight loss7.Severe weight loss a.Jejuno-ileal bypassa.Jejuno-ileal bypass b.Gastric bypassb.Gastric bypass c.Severe starvationc.Severe starvation8.Iatrogenic8.Iatrogenic a.Amiodaronea.Amiodarone b.Diltiazemb.Diltiazem c.Tamoxifenc.Tamoxifen d.Steroidsd.Steroids e.HAARTe.HAART f. tetracyclinef. tetracycline g.glucosamineg.glucosamine9.Refeeding syndrome9.Refeeding syndrome10.Exposure to toxic agents10.Exposure to toxic agents a.Environmenta.Environment b.Workplace – Sb,Th,Bab.Workplace – Sb,Th,Ba
NASHNASH
Affects 3.5-5% of the populationAffects 3.5-5% of the population
The rates of progression to cirrhosis have been The rates of progression to cirrhosis have been estimated at between 5% and 20% over 10 years.estimated at between 5% and 20% over 10 years.
There aren't any non-invasive means of predicting which There aren't any non-invasive means of predicting which patients are at risk of progression, and there are no patients are at risk of progression, and there are no agreed guidelines on how to monitor progression.agreed guidelines on how to monitor progression.
Natural historyNatural historyNatural historyNatural history
Simple steatosis: relatively benign “liver” prognosis with Simple steatosis: relatively benign “liver” prognosis with a risk of developing clinical evidence of cirrhosis over a risk of developing clinical evidence of cirrhosis over 15–20 years in the order of 1%–2%.15–20 years in the order of 1%–2%.
NASH and fibrosis: risk of progress to cirrhosis between NASH and fibrosis: risk of progress to cirrhosis between 0% at 5 years to 12% over 8 years. 0% at 5 years to 12% over 8 years.
Cirrhotic: high risk of developing hepatic Cirrhotic: high risk of developing hepatic decompensation and of dying from a liver-related cause decompensation and of dying from a liver-related cause including HCC.including HCC.
Initial InvestigationInitial Investigation
Look for risk factorsLook for risk factors BMI, DM, HBP, Lipids,FHx, Drugs, AlcoholBMI, DM, HBP, Lipids,FHx, Drugs, Alcohol
Liver screen (to exclude other diseases)Liver screen (to exclude other diseases) Including Glc/GTT/HbA1c/Lipids/ASTIncluding Glc/GTT/HbA1c/Lipids/AST Pl, Alb, INRPl, Alb, INR
USSUSS Spleen size, fatty liver, collateralsSpleen size, fatty liver, collaterals
Fibroscan® Fibroscan® Electronic platformElectronic platform
Ultrasonic signals acquisitionUltrasonic signals acquisition Numerical signal processingNumerical signal processing
Integrated computerIntegrated computer Stiffness measurementStiffness measurement Examinations databaseExaminations database
Dedicated probes with unique Dedicated probes with unique technologytechnology
Vibrator (50 Hz)US Transducer
(3,5 MHz)
Fibroscan® (Echosens, Paris, France)
Position of probe & explored volumePosition of probe & explored volume
Cylinder of 1 cm wide & 4 cm long
From 25 mm to 65 mm below skin surface
This volume is at least 100 times bigger than a biopsy sample
Results
Stiffness (kPa)
Median value of 10 shots
3.9 Kilo Pascals
At least 10 shots
Success Rate: ≥ 60%
IQR * (kPa)
Interval around median
Contains 50% of valid shots
≤ 25% of median value
NASH ManagementNASH Management
1) 1) All patientsAll patients should be encouraged to exercise, as there is good evidence should be encouraged to exercise, as there is good evidence that even in the absence of weight loss exercise improves NASH.that even in the absence of weight loss exercise improves NASH.
Obese PatientsObese PatientsWeight reducing diet (aim for 10%, 1-2lb per week)Weight reducing diet (aim for 10%, 1-2lb per week)In patients with BMI>28 with risk factors, or >30 without risk factors, In patients with BMI>28 with risk factors, or >30 without risk factors, consider treatment with Orlistat etc.consider treatment with Orlistat etc.
2) 2) Diabetic PatientsDiabetic PatientsGood diabetic control (HbA1c <6.5%) Good diabetic control (HbA1c <6.5%) Metformin Metformin ThiazolidinedionesThiazolidinedionesDietician for re-education.Dietician for re-education.Diabetologist if glucose control is difficult. Diabetologist if glucose control is difficult.
NASH ManagementNASH Management
3) 3) Patients with Hyperlipidaemia and abnormal LFT’sPatients with Hyperlipidaemia and abnormal LFT’s
Dyslipidaemia should be aggressively addressedDyslipidaemia should be aggressively addressed
Dietician ReviewDietician Review
Hypercholesterolaemia -Statins Hypercholesterolaemia -Statins
Hypertriglycerideaemia -Fibrate. Hypertriglycerideaemia -Fibrate.
Lipid ClinicLipid Clinic
Avoid DrugsAvoid Drugs
amiodarone, glucocorticoids, methotrexate, nifedipine, synthetic amiodarone, glucocorticoids, methotrexate, nifedipine, synthetic estrogens, tamoxifenestrogens, tamoxifen
Antioxidants?Antioxidants?
Alcohol Related Deaths Alcohol Related Deaths E&W 1979-2010E&W 1979-2010
http://www.statistics.gov.uk/cci/nugget.asp?id=1091
Mon
thly
adm
issi
on r
ate
UHL Alcohol Admissions 2004-8UHL Alcohol Admissions 2004-8
Spectrum of Alcoholic Liver DiseaseSpectrum of Alcoholic Liver Disease
The most common manifestations of alcoholic The most common manifestations of alcoholic liver disease are:liver disease are:
Alcoholic steato-hepatitisAlcoholic steato-hepatitis Acute alcoholic hepatitisAcute alcoholic hepatitis Cirrhosis due to alcoholCirrhosis due to alcohol
Alcoholic HepatitisAlcoholic Hepatitis
Most florid manifestation of ALDMost florid manifestation of ALD Cholestatic liver disease associated with the long term Cholestatic liver disease associated with the long term
heavy use of alcoholheavy use of alcohol Often a precursor to the development of cirrhosisOften a precursor to the development of cirrhosis More severe forms are associated with a high mortalityMore severe forms are associated with a high mortality 1yr mortality after initial hospitalisation is 40%1yr mortality after initial hospitalisation is 40%
Best treatmentBest treatment Stop drinkingStop drinking Resolution occurs within weeks-months +/- cirrhosisResolution occurs within weeks-months +/- cirrhosis
SymptomsSymptoms
FeverFever HepatomegalyHepatomegaly JaundiceJaundice CoagulopathyCoagulopathy Features of hepatic decompensationFeatures of hepatic decompensation
However, milder forms of alcoholic hepatitis However, milder forms of alcoholic hepatitis often do not cause any symptomsoften do not cause any symptoms
InvestigationInvestigation
BiochemistryBiochemistry AST/ALT ratio >1.5AST/ALT ratio >1.5 ALT usually <100 IU/mlALT usually <100 IU/ml Raised Raised GT (variable)GT (variable) Raised ALP (variable)Raised ALP (variable) Low Albumin (advanced Low Albumin (advanced
disease)disease)
Bilirubin (≥80 mmol/l)Bilirubin (≥80 mmol/l)
HaematologyHaematology Prolonged INR Prolonged INR
(advanced disease)(advanced disease) Macrocytosis / Macrocytosis /
anaemiaanaemia LeukocytosisLeukocytosis Thrombocytopenia Thrombocytopenia
(advanced disease)(advanced disease)
Glasgow Alcoholic Hepatitis ScoreGlasgow Alcoholic Hepatitis Score
Age <50 ≥ 50
WCC(109/l) <15 ≥15
Urea (mmol/l)<5 ≥5
PT ratio <1.5 1.5-2.0 >2.0
Bili (mol/l) <125 125-250 >250
Score 1 2 3
Patients score from 5-12 points.
Score >8 was used to define the high risk population and maximised sensitivity and specificity.
Survival from Alcoholic HepatitisSurvival from Alcoholic Hepatitis
28 day survival (%) 84 day survival(%)Day 1
GAHS <9 87 79 GAHS ≥9 46 40
Day 7
GAHS<9 93 86GAHS ≥9 47 37
Derivation and validation datasets combined – 436 patients
CorticosteroidsCorticosteroids
If the patient has severe alcoholic hepatitis If the patient has severe alcoholic hepatitis mDF>32, MELD >11, GAHS>8mDF>32, MELD >11, GAHS>8
Therapeutic trial of prednisolone 40mg POTherapeutic trial of prednisolone 40mg PO
7 days7 days
If no improvement in bilirubin then discontinueIf no improvement in bilirubin then discontinueMathurin P Mathurin P HepatolHepatol
2003;38;1363-92003;38;1363-9
Louvet A Louvet A HepatolHepatol 2008;45:1348-542008;45:1348-54
PentoxifyllinePentoxifylline
PTX is a phosphodiesterase inhibitor which modulates PTX is a phosphodiesterase inhibitor which modulates the transcription of the TNFthe transcription of the TNFαα-gene, lowers blood -gene, lowers blood viscosity and reduces portal hypertension.viscosity and reduces portal hypertension.
RCT RCT 101 patients with severe alcoholic hepatitis (mDF>32).101 patients with severe alcoholic hepatitis (mDF>32). Given 400mg tds for 28 days vs placeboGiven 400mg tds for 28 days vs placebo Mortality 24% vs 46% at 28 daysMortality 24% vs 46% at 28 days Significant reduction in hepatorenal syndromeSignificant reduction in hepatorenal syndrome
Acriviadis E, Gastro 2000 119;1637-48
3) ALP Elevated3) ALP Elevated
Cholestatic Illness Cholestatic Illness ((With or without jaundice)With or without jaundice)
Differentiate from Bony ALPDifferentiate from Bony ALP
GGT, ALP iso-enzymesGGT, ALP iso-enzymes
Investigation of CholestasisInvestigation of Cholestasis
Dilated bile ducts
Non-dilated bile ducts
Full liver screen
Raised ALP
Check GT if isolated rise
1) Stop alcohol
2) Stop hepatotoxic drugs
3) Advise weight loss if BMI>25
4) Recheck LFT’s after an interval
Persistently raised ALP
ConsiderMRCPERCP
Other imaging
Diagnosis made-Treat disease
Non diagnostic Ix-consider
Liver biopsy
Liver ALP ElevatedLiver ALP Elevated Cholestatic IllnessCholestatic Illness
AcuteAcute
CBD stones/GallstonesCBD stones/Gallstones Tumours 1Tumours 1ºº or 2 or 2ºº Pancreatic pathologyPancreatic pathology DrugsDrugs InfiltrationInfiltration SODSOD
ChronicChronic
PBCPBC Sclerosing CholangitisSclerosing Cholangitis
• 11ºº or 2 or 2ºº NASHNASH αα-1 antitrypsin-1 antitrypsin SarcoidSarcoid AmyloidAmyloid HIVHIV
Drug Induced CholestasisDrug Induced Cholestasis Intrahepatic Hepatocellular Cholestasis Intrahepatic Hepatocellular Cholestasis
Intrahepatic Ductular cholestasisIntrahepatic Ductular cholestasis
DuctopenicDuctopenic
GranulomatousGranulomatous
AllopurinolAllopurinolAntithyroid agentsAntithyroid agentsAugmentinAugmentinAzathioprineAzathioprineBarbituratesBarbituratesCaptoprilCaptoprilCarbamezepineCarbamezepineChlorpromazineChlorpromazineChlorpropamideChlorpropamideClindamycinClindamycinClofibrateClofibrateDiltiazemDiltiazemErythromycin estolateErythromycin estolateFlucloxacillinFlucloxacillinIsoniazidIsoniazidLisinoprilLisinoprilMethyltestosteroneMethyltestosteroneOral contraceptives (containing estrogens)Oral contraceptives (containing estrogens)Oral hypoglycemics Oral hypoglycemics PhenytoinPhenytoinTrimethoprim-sulfamethoxazole Trimethoprim-sulfamethoxazole